Adolescence in humans is a period of life when alcohol use is often initiated. Unfortunately, it is also a time when some individuals develop long-lasting patterns of alcohol abuse and alcoholism. Human and animal studies have revealed that during adolescence, brain areas such as the prefrontal cortex (PFC) are undergoing significant, yet normal, changes in synaptic connectivity. These changes in synaptic organization have important implications in the adolescent and adult PFC. For example, in a recent report (Markam et al., 2007), we demonstrated region- and sex-specific decreases in the number of neurons in the medial PFC (mPFC) of adolescent compared to adult rats. It is possible that alcohol alters these normal patterns of adolescent-to adult changes in mPFC and thereby produces a particularly susceptible nervous system. Furthermore, pubertal hormones may interact with alcohol's effects in the mPFC, and this might contribute to sex differences in drinking behavior. In the research proposed here, we will use animal models to explore the effects of alcohol exposure during adolescence on the mPFC and on the operant self-administration of alcohol in adulthood. This will be accomplished by: (1) examining whether alcohol exposure during adolescence alters decreases in neuron number in the rat mPFC and if gonadal hormones contribute to alcohol's effects; and (2) investigate whether alcohol exposure during adolescence alters alcohol drinking behavior in adulthood and if there is an influence of sex and hormonal status. Rats will be divided into eight different groups (n = 10/group) based on sex (male or female), hormone status (intact or pre-pubertal gonadectomy), and adolescent exposure to alcohol (saline or 3.0 g/kg ethanol). As adults (PND 90), rats will be either euthanized for brain removal and subsequent stereological analysis of the number of neurons in the mPFC (Aim 1) or they will begin training for operant self-administration of alcohol (Aim 2). Ultimately, the information learned in these studies will help us understand if alcohol-induced brain changes are a contributing factor to the high rates of alcoholism in individuals who begin drinking at an early age. [unreadable] [unreadable] [unreadable]